The Breast Cancer Biology Group is committed to translational research. It studies the molecular and phenotypic changes that occur in breast cancer with the aim of translating the findings into clinical applications. The laboratory has a particular focus on two areas of research:

1. The changes that occur in O-linked glycosylation in breast cancer. This area of research was initiated from our studies on the mucin MUC1, which is over expressed and aberrantly glycosylated in breast cancer.  We also have had long standing interest in the use of MUC1 as a target for immunotherapy, including the targeting of MUC1 HLA-A2 Class I peptides to dendritic cells via DNGR-1. The involvement of aberrant O-linked glycosylation in the development and progression of breast cancers is a major focus.
2. Epigenetic changes associated with histone demethylation. KDM5B a histone demethylase that is expressed in breast cancers and the developing mammary gland where it is required for normal development.

Glycosylation

• Glycosylation of proteins is one of the most common forms of post-translational modification and affects many cellular functions including cell:cell interactions, cell:matrix interactions, molecular recognition as well as the stability and folding of proteins. Thus for a cell to have a "normal" behaviour its glycosylation machinery must be working correctly
• The change to malignancy is associated with changes in the glycans attached to glycolipids and glycoproteins and evidence is now accumulating that this can have a fundamental effect on the tumour cell. The particular form glycosylation of proteins that we are studying is O-linked glycosylation, where glycans are O-linked to serine and/or threonine and the sugars are added individually and sequentially. This type of glycosylation is found on mucin-type molecules or glycoproteins containing mucin-like domains. Our previous work has demonstrated that changes in the expression of glycosyltransferases in breast carcinomas compared to normal breast epithelial can explain, at least in part, the changes in O-linked glycans observed in breast cancers. In particular, two sialyltransferases are upregulated at the RNA level.
• We have particularly been studying the membrane mucin known as MUC1, which is upregulated and aberrantly expressed in breast and other carcinomas. The staining of an antibody that specifically recognises MUC1 carrying tumour-associated glycans shows that greater than 90% of breast carcinomas aberrantly glycosylate their O-linked glycans, suggesting that this may elicit some benefit to the tumour.

Projects

• There are various projects within the laboratory looking at the affects of changes in glycosylation on tumour cells and on the tumour environment, and studying the function of KDM5B.
• We are investigating the how the changes in O-linked glycosylation affects the development of mammary cancer using model systems.
• We are investigating how O-linked glycosylation affects the progression of breast cancer and if the expression of particular glycosylated proteins can influence the site of metastasis. We are also investigating, using in vitro models of the bone marrow niche, how O-linked glycans affect the interaction of breast cancer cells with this niche.
• We are looking at how particular tumour-associated glycoforms of MUC1 interact with immune cells to stimulate an immune response and suppress an immune response.
• We are investigating how aberrant glycosylation of specific glycoproteins influences signalling of EGFR and the growth of tumours.
• KDM5B binds to the estrogen receptor and so we are investigating its role in estrogen receptor signalling and its function in mammary gland development.
• We are investigating enhancing the efficacy of and overcoming resistance to HER-2 targeted therapy by inhibiting KDM5B demethylase activity.

Breast cancer; post-translational modifications; glycobiology; how changes in glycosylation in breast cancer influences metastasis; glycoprotein:lectin interactions; immunotherapy; epigenetics particularly histone demethylases.

Postgraduate Co-ordinator for Division of Cancer Studies (Guy's Campus).